A receptor is a biological structure with one or more binding domains that reversibly complexes with one or more ligands, where that complexation has biological consequences. Receptors can exist entirely outside the cell (extracellular receptors), within the cell membrane (but presenting sections of the receptor to the extracellular milieu and cytosol), or entirely within the cell (intracellular receptors). They may also function independently of a cell (e.g., clot formation). Receptors within the cell membrane allow a cell to communicate with the space outside of its boundaries (i.e., signaling) as well as to function in the transport of molecules and ions into and out of the cell.
A ligand is a binding partner for a specific receptor or family of receptors. A ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool.
The super family of seven transmembrane proteins (7-TMs), also called G-protein coupled receptors (GPCRs), represents one of the most significant classes of membrane bound receptors that communicate changes that occur outside of the cell""s boundaries to its interior, triggering a cellular response when appropriate. The G-proteins, when activated, affect a wide range of downstream effector systems both positively and negatively (e.g., ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins, and the like).
Muscarinic receptors are members of the G-protein coupled receptors that are composed of a family of five receptor sub-types (M1, M2, M3, M4 and M5) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor subtypes in the brain and other organs has been documented (Bonner, T. I. et al., Science (Washington D.C.) 1987, 237, 527-532; Goyal, R. K., J. Med., 1989, 321, 1022; Hulme, E. C., et al., Annu. Rev. harmacol. Toxicol. 1990, 30, 633; and Eglen, R. M. and Hegde, S. S., Drug News Perspect. 1997, 10(8), 462-469). For example, the smooth muscle is composed largely of M2 and M3 receptors, cardiac muscle is composed largely of M2 receptors, and salivary glands are largely composed of M3 receptors.
It has been established that the muscarinic receptors are involved in diseases such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and alzheimer,s disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, and hyper salvation syndromes (Fisher, A., Invest. Drugs, 1997, 6(10), 1395-1411; Martel, A. M., et al., Drugs Future, 1997, 22(2), 135-137; Graul, A. and Castaner, J., Drugs Future, 1996, 21(11), 1105-1108; and Graul, A., et al., Drugs Future, 1997, 22(7), 733-737).
A number of compounds having muscarinic receptor antagonistic activities are being used to treat these diseases. For example, oxybutynin is being used for the treatment of urinary urge incontinence and dicyclorine is being used for the treatment of irritable bowel syndrome. However, these drugs have limited utility as they produce side effects such as dry mouth, blurred vision, and mydriasis.
There is currently a need for novel muscarinic receptor antagonists.
The invention is directed to urea derivatives that are muscarinic receptor antagonists and agonists and that are useful in the treatment and prevention of diseases mediated by muscarinic receptors (e.g. chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like).
Accordingly, the invention provides a compound of the invention which is a compound of Formula (I):
L1xe2x80x94Xxe2x80x94L2
wherein: 
wherein:
A is an aryl or a heteroaryl ring;
Bxe2x80x3 is xe2x80x94NRaxe2x88x92 wherein Ra is hydrogen, alkyl, aryl, heteroaryl, or substituted alkyl;
R1 is hydrogen or alkyl;
R2 is Het, or is selected from a group consisting of formula (i), (ii), and (iii): 
wherein:
xe2x80x94xe2x80x94 is an optional double bond;
n1 is an integer of from 1 to 4;
n2 is an integer of from 1 to 3;
V is xe2x80x94CHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)n3xe2x80x94 (where n3 is an integer of from 0 to 2), or xe2x80x94NR4xe2x80x94 (wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);
xe2x80x9cHetxe2x80x9d is a heteroaryl ring which optionally attaches (a) to a linker;
R3 is hydrogen, alkyl, amino, substituted amino, xe2x80x94ORa (where Ra is hydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;
R5 is hydrogen, alkyl, amino, substituted amino, xe2x80x94ORb (where Rb is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker;
R6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching (a) to a linker;
K is a bond or an alkylene group;
Kxe2x80x3 is a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)n4xe2x80x94 (where n4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and
B is heterocycloamino or heteroarylamino, which optionally attaches (a) to a linker;
provided that at least one of the R5, R6, R7, R8, xe2x80x9cHetxe2x80x9d, heterocycloamino or heteroarylamino groups attaches (a) to a linker;
X is a linker;
L2 is a group selected from a group consisting of:
(i) a group of formula (b): 
wherein:
Dxe2x80x3 is alkylene;
D is xe2x80x94NR31R32, xe2x80x94N+(R33R34R35) or xe2x80x94OR32 where R31, R33, and R34 are, independently of each other, hydrogen, alkyl, or aralkyl; and R32 and R35 represent a covalent bond attaching (b) to a linker;
R27 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
R28 is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
R29 and R30 are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino; or
one of R27, R28, R29, or R30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group;
(ii) a group of formula (c): 
wherein:
n11 is an integer of from 1 to 7;
n12 is 0 to 7;
F is xe2x80x94NR40xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CHR41xe2x80x94 (wherein R40 and R41 are, independently of each other, hydrogen, alkyl, or substituted alkyl);
Fxe2x80x3 is a covalent bond, xe2x80x94OR43, xe2x80x94NR42R43, or xe2x80x94N+R43R44R45 wherein R42 is hydrogen or alkyl, R44 and R45 are alkyl, and R43 is hydrogen, alkyl, or a covalent bond attaching (c) to a linker;
R36 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
R37 is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; and
R38 is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R38 and R43 attaches (c) to a linker;
R39 is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; and
(iii) a group of formula (d) or (e): 
wherein:
R46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;
R47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or xe2x80x94COOR50 where R50 is alkyl; or
R46 and R47 together with the nitrogen atom to which they are attached form heterocycle, which heterocycle, in addition to optionally bearing the optional substituents defined hereinbelow for a heterocycle, can also optionally be substituted with one or more (e.g. 1, 2, 3, or 4) alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
R48 is a covalent bond that attaches the (d) or the (e) to a linker; and
R49 is alkyl;
or a pharmaceutically acceptable salt; or prodrug thereof.
Preferably X is a group of formula:
xe2x80x94Xaxe2x80x94Zxe2x80x94(Yaxe2x80x94Z)mxe2x80x94Ybxe2x80x94Zxe2x80x94Xaxe2x80x94
wherein
m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94,xe2x80x94NRxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NRxe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94C(S)Oxe2x80x94, xe2x80x94C(S)NRxe2x80x94 or a covalent bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Ya and Yb at each separate occurrence are selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94,xe2x80x94NRxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2C(O)xe2x80x94, xe2x80x94NRxe2x80x2C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2C(S)NRxe2x80x2xe2x80x94, xe2x80x94C(xe2x80x94NRxe2x80x2)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(xe2x80x94NRxe2x80x2)xe2x80x94, xe2x80x94OC(O)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x80x94C(Rxe2x80x3)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(Rxe2x80x3)xe2x80x94Nxe2x80x94,xe2x80x94P(O)(ORxe2x80x2)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94P(O)(ORxe2x80x2), S(O)nCRxe2x80x2Rxe2x80x3xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94S(O)nxe2x80x94,xe2x80x94Sxe2x80x94Sxe2x80x94, and a covalent bond; where n is 0, 1 or 2; and R, Rxe2x80x2 and Rxe2x80x3 at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic (preferably, at least one of Xa, Ya, Yb or Z is not a covalent bond).
The invention also provides a compound of the invention which is a compound of formula (IV): 
wherein R2, Kxe2x80x3, A, K, R1, Bxe2x80x3, B, X, and L2 have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof. A preferred compound of the invention is a compound of formula (IVa): 
wherein X, and L2 have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof.
The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof.
The invention also provides synthetic intermediates disclosed herein, as well as synthetic methods useful for preparing such intermediates, and synthetic methods useful for preparing compounds of the invention or salts thereof.
The invention also provides a method of treating diseases mediated by a muscarinic receptor in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof.
The invention also provides a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof for use in medical therapy, as well as the use of a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for the treatment of a disease mediated by a muscarinic receptor in a mammal.
Applicant has discovered that urea compounds of the present invention are metabolically more stable than compounds lacking such a urea functionality. Accordingly, compounds of the present invention have longer metabolic half-lives and/or longer duration of action in vivo, which can reduce the dose required for administration or can reduce the likelihood of the generation of unwanted metabolites.
The following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings.
The term xe2x80x9calkylxe2x80x9d refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group as defined above wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94 (where n is 0 to 2), xe2x80x94NRxe2x80x94 (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl, and xe2x80x94NRaRb, wherein Ra and Rb may be the same or different and and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. This term is exemplified by groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl, 2-sulfonamidoethyl, 2-carboxyethyl, and the like.
The term xe2x80x9calkylenexe2x80x9d refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), the propylene isomers (e.g., xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH(CH3)CH2xe2x80x94) and the like.
The term xe2x80x9csubstituted alkylenexe2x80x9d refers to an alkylene group, as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused groups contain from 1 to 3 fused ring structures.
The term xe2x80x9calkylaminoalkylxe2x80x9d, xe2x80x9calkylaminoalkenylxe2x80x9d and xe2x80x9calkylaminoalkynylxe2x80x9d refers to the groups RaNHRbxe2x80x94 where Ra is alkyl group as defined above and Rb is alkylene, alkenylene or alkynylene group as defined above. Such groups are exemplified by 3-methylaminobutyl, 4-ethylamino-1,1-dimethylbutyn-1-yl, 4-ethylaminobutyn-1-yl, and the like.
The term xe2x80x9calkarylxe2x80x9d or xe2x80x9caralkylxe2x80x9d refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to the groups alkyl-Oxe2x80x94, alkenyl-Oxe2x80x94, cycloalkyl-Oxe2x80x94, cycloalkenyl-Oxe2x80x94, and alkynyl-Oxe2x80x94, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferred alkoxy groups are alkyl-Oxe2x80x94 and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
The term xe2x80x9csubstituted alkoxyxe2x80x9d refers to the groups substituted alkyl-Oxe2x80x94, substituted alkenyl-Oxe2x80x94, substituted cycloalkyl-Oxe2x80x94, substituted cycloalkenyl-Oxe2x80x94, and substituted alkynyl-Oxe2x80x94 where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
The term xe2x80x9chaloalkoxyxe2x80x9d refers to the groups alkyl-Oxe2x80x94 wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
The term xe2x80x9calkylalkoxyxe2x80x9d refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way of example, methylenemethoxy (xe2x80x94CH2OCH3), ethylenemethoxy (xe2x80x94CH2CH2OCH3), n-propylene-iso-propoxy (xe2x80x94CH2CH2CH2OCH(CH3)2), methylene-t-butoxy (xe2x80x94CH2xe2x80x94Oxe2x80x94C(CH3)3), and the like.
The term xe2x80x9calkylthioalkoxyxe2x80x9d refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, by way of example, methylenethiomethoxy (xe2x80x94CH2SCH3), ethylenethiomethoxy (xe2x80x94CH2CH2SCH3), n-propylene-iso-thiopropoxy (xe2x80x94CH2CH2CH2SCH(CH3)2), methylene-t-thiobutoxy (xe2x80x94CH2SC(CH3)3), and the like.
The term xe2x80x9calkenylxe2x80x9d refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. Preferred alkenyl groups include ethenyl (xe2x80x94CHxe2x95x90CH2), n-propenyl (xe2x80x94CH2CHxe2x95x90CH2), iso-propenyl (xe2x80x94C(CH3)xe2x95x90CH2), and the like.
The term xe2x80x9csubstituted alkenylxe2x80x9d refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9calkenylenexe2x80x9d refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. This term is exemplified by groups such as ethenylene (xe2x80x94CHxe2x95x90CHxe2x80x94), the propenylene isomers (e.g., xe2x80x94CH2CHxe2x95x90CHxe2x80x94 or xe2x80x94C(CH3)xe2x95x90CHxe2x80x94), and the like.
The term xe2x80x9csubstituted alkenylenexe2x80x9d refers to an alkenylene group as defined above having from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl. Additionally, such substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkenylene group.
The term xe2x80x9calkynylxe2x80x9d refers to a monoradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 20 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl (xe2x80x94Cxe2x89xa1CH), propargyl (xe2x80x94CH2Cxe2x89xa1CH), and the like.
The term xe2x80x9csubstituted alkynylxe2x80x9d refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl.
The term xe2x80x9calkynylenexe2x80x9d refers to a diradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynylene groups include ethynylene (xe2x80x94Cxe2x89xa1Cxe2x80x94), propargylene (xe2x80x94CH2Cxe2x89xa1Cxe2x80x94), and the like.
The term xe2x80x9csubstituted alkynylenexe2x80x9d refers to an alkynylene group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9cacylxe2x80x9d refers to the groups HC(O)xe2x80x94, alkyl-C(O)xe2x80x94, substituted alkyl-C(O)xe2x80x94, cycloalkyl-C(O)xe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, cycloalkenyl-C(O)xe2x80x94, substituted cycloalkenyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94 and heterocyclic-C(O)xe2x80x94 where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term xe2x80x9cacylaminoxe2x80x9d or xe2x80x9caminocarbonylxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term xe2x80x9caminoacylxe2x80x9d refers to the group xe2x80x94NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term xe2x80x9caminoacyloxyxe2x80x9d or xe2x80x9calkoxycarbonylaminoxe2x80x9d refers to the group xe2x80x94NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term xe2x80x9cacyloxyxe2x80x9d refers to the groups alkyl-C(O)Oxe2x80x94, substituted alkyl-C(O)Oxe2x80x94, cycloalkyl-C(O)Oxe2x80x94, substituted cycloalkyl-C(O)Oxe2x80x94, aryl-C(O)Oxe2x80x94, heteroaryl-C(O)Oxe2x80x94, and heterocyclic-C(O)Oxe2x80x94 wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term xe2x80x9carylxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
The term xe2x80x9caryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
The term xe2x80x9carylenexe2x80x9d refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.
The term xe2x80x9caminoxe2x80x9d refers to the group xe2x80x94NH2.
The term xe2x80x9csubstituted aminoxe2x80x9d refers to the group xe2x80x94NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic provided that both R""s are not hydrogen.
The term xe2x80x9ccarboxyalkylxe2x80x9d or xe2x80x9calkoxycarbonylxe2x80x9d refers to the groups xe2x80x9cxe2x80x94C(O)O-alkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-substituted alkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-cycloalkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-substituted cycloalkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-alkenylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-substituted alkenylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-alkynylxe2x80x9d and xe2x80x9cxe2x80x94C(O)O-substituted alkynylxe2x80x9d where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl alkynyl are as defined herein.
The term xe2x80x9ccycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
The term xe2x80x9csubstituted cycloalkylxe2x80x9d refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9ccycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl, and the like.
The term xe2x80x9csubstituted cycloalkenylxe2x80x9d refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring). Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
The term xe2x80x9cheteroaralkylxe2x80x9d refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. Such heteroaralkyl groups are exemplified by pyridylmethyl, pyridylethyl, indolylmethyl, and the like.
The term xe2x80x9cheteroaryloxyxe2x80x9d refers to the group heteroaryl-Oxe2x80x94.
The term xe2x80x9cheteroarylenexe2x80x9d refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6-pyridylene, 2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-pyridnylene, 2,5-indolenyl, and the like.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d or refers to a monoradical saturated unsaturated group having a single ring or multiple condensed rings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl, and the like.
Examples of nitrogen heteroaryls and heterocycles include, but are not limited to, pyrrole, thiophene, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, pyrrolidine, piperidine, piperazine, indoline, morpholine, tetrahydrofuranyl, tetrahydrothiophene, and the like as well as N-alkoxy-nitrogen containing heterocycles.
The term xe2x80x9cheterocyclooxyxe2x80x9d refers to the group heterocyclic-Oxe2x80x94.
The term xe2x80x9cthioheterocyclooxyxe2x80x9d refers to the group heterocyclic-Sxe2x80x94.
The term xe2x80x9cheterocyclenexe2x80x9d refers to the diradical group formed from a heterocycle, as defined herein, and is exemplified by the groups 2,6-morpholino, 2,5-morpholino and the like.
xe2x80x9cHeteroarylaminoxe2x80x9d means a 5 membered aromatic ring wherein one or two ring atoms are N, the remaining ring atoms being C. The heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted amino, acylamino, xe2x80x94OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or xe2x80x94S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl]. More specifically the term heterocycloamino includes, but is not limited to, imidazole, pyrazole, benzimidazole and benzpyrazole.
xe2x80x9cHeterocycloaminoxe2x80x9d means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one or two additional ring heteroatoms selected from the group consisting of N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted amino, acylamino, xe2x80x94OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or xe2x80x94S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl]. More specifically the term heterocycloamino includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, indolino, or thiomorpholino. The term heterocycloamino also includes, quinuclidine, 1-azabicyclo[2.2.1]heptyl, 1-azabicyclo[3.2.1]octyl and the derivatives thereof.
The term xe2x80x9coxyacylaminoxe2x80x9d or xe2x80x9caminocarbonyloxyxe2x80x9d refers to the group xe2x80x94OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9cspiro-attached cycloalkyl groupxe2x80x9d refers to a cycloalkyl group attached to another ring via one carbon atom common to both rings.
The term xe2x80x9cthiolxe2x80x9d refers to the group xe2x80x94SH.
The term xe2x80x9cthioalkoxyxe2x80x9d or xe2x80x9calkylthioxe2x80x9d refers to the group xe2x80x94S-alkyl.
The term xe2x80x9csubstituted thioalkoxyxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
The term xe2x80x9cthioaryloxyxe2x80x9d refers to the group aryl-Sxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
The term xe2x80x9cthioheteroaryloxyxe2x80x9d refers to the group heteroaryl-Sxe2x80x94 wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
As to any of the above groups which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
Unless specified otherwise, all ranges referred to herein include the stated end-point values.
The term xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d refers to salts which retain biological effectiveness and are not biologically or otherwise undesirable. In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
Pharmaceutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like.
Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
The term xe2x80x9cpharmaceutically-acceptable cationxe2x80x9d refers to the cation of a pharmaceutically-acceptable salt.
The term xe2x80x9cprotecting groupxe2x80x9d or xe2x80x9cblocking groupxe2x80x9d refers to any group which when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product. Preferred removable thiol blocking groups include disulfide groups, acyl groups, benzyl groups, and the like. Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxy-carbonyl (FMOC), allyloxycarbonyl (ALOC), and the like which can be removed by conventional conditions compatible with the nature of the product. Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild conditions compatible with the nature of the product.
The term xe2x80x9coptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event, circumstance or substituent may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term xe2x80x9cinert organic solventxe2x80x9d or xe2x80x9cinert organic solventxe2x80x9d means a solvent which is inert under the conditions of the reaction being described in conjunction therewith including, by way of example only, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, t-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert solvents.
The term xe2x80x9ctreatmentxe2x80x9d refers to any treatment of a pathologic condition in a mammal, particularly a human, and includes:
(i) preventing the pathologic condition from occurring in a subject which may be predisposed to the condition but has not yet been diagnosed with the condition and, accordingly, the treatment constitutes prophylactic treatment for the disease condition;
(ii) inhibiting the pathologic condition, i.e., arresting its development;
(iii) relieving the pathologic condition, i.e., causing regression of the pathologic condition; or
(iv) relieving the conditions mediated by the pathologic condition.
The term xe2x80x9cpathologic condition which is modulated by treatment with a ligandxe2x80x9d covers all disease states (i.e., pathologic conditions) which are generally acknowledged in the art to be usefully treated with a ligand for the muscarinic receptors in general, and those disease states which have been found to be usefully treated by a compound of the invention. Such disease states include, by way of example only, the treatment of a mammal afflicted with chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to that amount of a compound which is sufficient to effect treatment, as defined above, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
The term xe2x80x9clinkerxe2x80x9d, identified by the symbol xe2x80x98Xxe2x80x99 refers to a group or groups that covalently attaches L1 and L2. Additionally, the linker can be either a chiral or achiral molecule. The term xe2x80x9clinkerxe2x80x9d does not, however, extend to cover solid inert supports such as beads, glass particles, fibers, and the like. But it is understood that the compounds of this invention can be attached to a solid support if desired. For example, such attachment to solid supports can be made for use in separation and purification processes and similar applications.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) may be preferred. Specific and preferred values listed herein for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents
A preferred value for A is phenyl or pyridine
A preferred value for R1 is hydrogen methyl, or ethyl.
Another preferred value for R1 is hydrogen.
A preferred value for R2 is pyrrolyl, pyridinyl, or imidazolyl.
Another preferred value for R2 is phenyl.
A preferred value for V is xe2x80x94CHxe2x80x94 or xe2x80x94NR4xe2x80x94 (wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl).
A preferred value for R3 is hydrogen or alkyl
A preferred value for R5 is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker
Another preferred value for R5 is hydrogen, methyl, phenyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino, benzyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino.
A preferred value for R6, R7, and R8 independent of each other is hydrogen, alkyl, nitro, hydroxy, or amino.
A preferred value for K is alkylene having from 1 to 10 carbon atoms.
A preferred value for K is alkylene having from 1 to 5 carbon atoms.
A preferred value for K is a bond or a methylene group.
A preferred value for Kxe2x80x3 is a bond.
A preferred value for Ra is hydrogen.
A preferred value for B is a heterocycloamino group which attaches (a) to a linker.
Another preferred value for B is a formula selected from a group consisting of formula (j), formula (k), and formula (l): 
wherein:
n13 and n14 are, independently of each other, an integer of from 0 to 4 provided that n13+n14 is an integer of from 3 to 5;
n15 and n17 are, independently of each other, an integer of from 0 to 4 provided that n15+n17 is an integer of from 3 to 5;
n16 is an integer of from 0 to 3 provided that n15+n16 is an integer of from 3 to 5;
n18, n19 and n20 are, independently of each other, an integer of from 0 to 3 provided that n18+n19+n20 is 2 or 3;
n21 is an integer of from 1 to 3;
Wa and Wc are, independently of each other: 
where:
n22 is 0 or 1;
R53 and R54 are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl, aralkyl, or heterocyclylalkyl or a covalent bond attaching (a) to a linker;
R55 is alkyl, alkenyl or alkynyl; and
Wb is xe2x80x94N(O)n23 or xe2x80x94N+xe2x80x94R56 where n23 is 0 or 1, and R56 is alkyl, alkenyl, alkynyl, or aralkyl, or a covalent bond attaching (a) to a linker;
provided that a carbon other than a bridge head carbon is bonded to Bxe2x80x3.
Another preferred value for B is a ring represented by the following general formulae: 
wherein a carbon atom other than a bridge head carbon is bound to Bxe2x80x3; and Wc is as defined above.
A more preferred value for B is pyrrolidine, piperidine, or hexahydroazepine attaching (a) to a linker.
Another more preferred value for B is piperidine wherein the nitrogen atom of said piperidine attaches (a) to a linker.
Another more preferred value for B is piperidin-4-yl wherein the nitrogen at the 1 position optionally attaches (a) to a linker.
Another more preferred value for B is quinuclidine, 1-azabicyclo[2.2.1]-heptyl, or 1-azabicyclo[3.2.1]octyl attaching (a) to a linker, wherein a carbon other than a bridge head carbon is bound to Bxe2x80x3.
A preferred value for Dxe2x80x3 is xe2x80x94(CH2)n43xe2x80x94 where n43 is an integer of from 1-10, preferably 2-8, more preferably 2-4. Another preferred value for n43 is an integer of from 3-10.
A preferred value for D is xe2x80x94NR31R32 or xe2x80x94N+(R33R34R35)Mxe2x88x92 where R31, R33, and R34 are, independently of each other, hydrogen or methyl, and R32 and R35 represent a covalent bond attaching (b) to a linker. More preferably R31, R33, and R34 methyl, and R32 and R35 represent a covalent bond attaching (b) to a linker.
A preferred value for R27 is hydrogen.
A preferred value for R28 is hydrogen.
A preferred value for R29 and R30 independently is hydrogen; or one of R27, R28, R29, or R30 together with the adjacent group forms a methylenedioxy or ethylenedioxy group.
A preferred value for n11 is 1.
A preferred value for n12 is 6.
A preferred value for F is xe2x80x94Oxe2x80x94.
A preferred value for Fxe2x80x3 is a covalent bond, xe2x80x94OR43, xe2x80x94NR42R43 wherein R42 is hydrogen or alkyl, or xe2x80x94N+(R43R44R45) wherein R44 and R45 are alkyl, and R43 is a covalent bond attaching (c) to a linker.
A preferred value for Fxe2x80x3 is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, N(CH3)xe2x80x94 or xe2x80x94N(CH3)2xe2x80x94
A more preferred value for Fxe2x80x3 is xe2x80x94NHxe2x80x94, N(CH3)xe2x80x94 or xe2x80x94N(CH3)2xe2x80x94 wherein the nitrogen atom attaches (c) to a linker.
A preferred value for R36 is hydrogen.
Preferably R37 is ortho to the xe2x80x94(CHR38)xe2x80x94 group and is hydrogen or alkoxy. More preferably R37 is ortho to the xe2x80x94(CHR38) group and is methoxy.
Preferably is R3 is hydrogen.
Preferably R39 is hydrogen.
Preferably L2 is a group of formula (d) wherein: R46 is alkyl or substituted alkyl; R47 is alkyl, substituted alkyl, or heterocycle; or R46 and R47 together with the nitrogen atom to which they are attached form heterocycle.
Preferably, L2 is a group of formula A1-A241 as shown in the following table. L2 is preferably linked to X through a non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of L2.
Preferably, L2 can also be a group of formula A301-A439 as shown in the following table. L2 is preferably linked to X through a non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of L2.
Preferably, L2 can also be a group of formula A501-A523 as shown in the following table. L2 is preferably linked to X through a non-aromatic nitrogen atom of L2.
A more preferred value for L2 is A234, A363, A364, A153, A28, A324, A329, A562, A87, or A239.
A preferred value for X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.
Another preferred value for X is an alkylene group having from 3 to 20 carbon atoms; wherein one or more carbon atoms (e.g. 1, 2, 3, or 4) in the alkylene group is optionally replaced with xe2x80x94Oxe2x80x94; and wherein the chain is optionally substituted on carbon with one or more hydroxyl (e.g. 1, 2, 3, or 4).
Another preferred value for X is an alkylene group having from 6 to 15 carbons atoms; wherein one or more carbon atoms (e.g. 1, 2, 3, 4) in the alkylene group is optionally replaced with xe2x80x94Oxe2x80x94; and wherein the chain is optionally substituted on carbon with one or more hydroxyl (e.g. 1, 2, 3, or 4).
Another preferred value for X is is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.
Another preferred value for X is a group of the following formula: 
wherein the phenyl ring is optionally substituted with 1, 2, or 3 fluoro groups.
Another preferred value for X is a group of one of the following formulae: 
A preferred group of compounds of formula (I) are compounds wherein R2 is selected from formula (i) and (iii); and wherein Kxe2x80x3 is a bond or methylene.
A preferred group of compounds of formula (I) are compounds wherein R2 is formula (i); R3 is hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, or trifluoromethyl; and Kxe2x80x3 is a bond or methylene.
A preferred group of compounds of formula (I) are compounds wherein R2 is formula (iii); R6, R7, and R8 are each hydrogen, methyl, ethyl, propyl, isopropyl, fluoro, or trifluoromethyl; and Kxe2x80x3 is a bond or methylene.
A preferred group of compounds are compounds of formula (I) wherein R46 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle; R47 is alkyl, substituted alkyl, aryl, acyl, heterocycle, or xe2x80x94COOR50 where R50 is alkyl; or R46 and R47 together with the nitrogen atom to which they are attached form heterocycle.
A preferred group of compounds are compounds of formula (I) wherein L2 is a group of formula (d) wherein R46 and R47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl xe2x80x94SO2-heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
A more preferred group of compounds are compounds of formula (I) wherein L2 is a group of formula (d) wherein R46 and R47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
A preferred group of compounds are compounds of formula (I) wherein L2 is a group of formula (d) wherein R46 and R47 together with the nitrogen atom to which they are attached form heterocycle which is substituted with 1 to 5 substituents independently selected from the group consisting of substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
A preferred group of compounds are compounds of formula (I) wherein L2 is a group of formula (d) wherein at least one of R46 and R47 individually, or R46 and R47 taken together, is a group that comprises a basic nitrogen atom (e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7).
A preferred group of compounds are compounds of formula (I) wherein L2 is a group of formula (d) wherein R46 is a heterocycle, optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and R47 is alkyl, substituted alkyl, acyl, or xe2x80x94COOR50.
A preferred group of compounds are compounds of formula (1) wherein L2 is a group of formula (d) wherein R46 is alkyl that is substituted by a group that comprises a basic nitrogen atom (e.g. a nitrogen atom with a pKa of preferably at least about 5, more preferably al least about 6, or most preferably at least about 7).
A preferred group of compounds are compounds of formula (I) wherein L2 is a group of formula (d) wherein R46 is alkyl that is optionally substituted with from 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, NRaRb, wherein Ra and Rb may be the same or different and and are chosen from hydrogen, alkyl, substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclic.
A preferred group of compounds are compounds of formula (I) wherein L2 is a group of formula (d) wherein R46 is a heterocycle which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl xe2x80x94SO2-heteroaryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
A preferred group of compounds are compounds of formula (I) wherein L2 is a group of formula (d) wherein R46 is 3-piperidinyl, 4-piperidinyl, or 3-pyrrolidinyl, which R46 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
A preferred group of compounds are compounds of formula (I) wherein R46 and R47 together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring which ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
A preferred group of compounds are compounds of formula (I) wherein R46 and R47 together with the nitrogen atom to which they are attached form a heterocycle that is an aza-crown ether (e.g. 1-aza-12-crown-4, 1-aza-15-crown-5, or 1-aza-18-crown-6).
A preferred group of compounds of formula (I) are compounds wherein: A is an aryl or a heteroaryl ring; Bxe2x80x3 is xe2x80x94NRaxe2x80x94 wherein Ra is hydrogen, alkyl, or substituted alkyl; R1 is hydrogen or alkyl; R2 is selected from a group consisting of formula (i), (ii), (iii), or xe2x80x9cHetxe2x80x9d:
wherein: xe2x80x94is an optional double bond; n, is an integer of from 1 to 4; n2 is an integer of from 1 to 3; V is xe2x80x94CHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)n3xe2x80x94 (where n3 is an integer of from 0 to 2), or xe2x80x94NR4xe2x80x94 (wherein R4 is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl); xe2x80x9cHetxe2x80x9d is a heteroaryl ring which optionally attaches the ligand to a linker; R3 is hydrogen, alkyl, amino, substituted amino, xe2x80x94ORa (where Ra is hydrogen, alkyl, or acyl), or a covalent bond attaching the ligand to a linker; R5 is hydrogen, alkyl, amino, substituted amino, xe2x80x94ORb (where Rb is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching the ligand to a linker; R6, R7, and R8 are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; K is a bond or an alkylene group; Kxe2x80x3 is a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)n4xe2x80x94 (where n4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and B is a heterocycloamino group which optionally attaches the ligand to a linker; provided that at least one of the R5, R6, R7, R8, xe2x80x9cHetxe2x80x9d, or the heterocycloamino group attaches the ligand to a linker.
A preferred compound of formula (I) is a compound of Formula (Ia): 
wherein A, R1, R2, K, Kxe2x80x3, B, X, R46 and R47 are as defined herein.
For a compound of Formula (Ia) a preferred group of compounds is that wherein A is phenyl or pyridine; and K and Kxe2x80x3 are bond.
For a compound of Formula (Ia) another preferred group of compounds is that wherein A is phenyl or pyridine; R2 is phenyl; and K and Kxe2x80x3 are bond.
For a compound of Formula (Ia) another preferred group of compounds is that wherein B has any of the preferred values identified herein.
The invention also provides a compound of formula (IV): 
wherein L2 is an organic group comprising at least one (e.g. 1, 2, 3, or 4) primary, secondary, or tertiary amines. Typically, the amine of L2 should be basic, having a pH of at least about 5, and preferably at least about 6, more preferably at least about 7. The nature of the group L2 is not critical provided the compound has suitable properties (e.g. solubility, stability, and toxicity) for its intended use (e.g. as a drug or as a pharmacological tool). Typically the group L2 will have a molecular weight below 500 and preferably below about 300. Additionally, the group L2 preferably comprises 5 or fewer hydrogen bond donors (e.g. OH, xe2x80x94NHRxe2x80x94, and xe2x80x94C(xe2x95x90O)NHRxe2x80x94) and ten or fewer hydrogen bond acceptors (e.g. xe2x80x94Oxe2x80x94, xe2x80x94NRRxe2x80x94, and xe2x80x94Sxe2x80x94). Preferably, the nitrogen of B shown in formula (IV) is separated from an amine of the group L2 by about 15 angstroms to about 75 angstroms (based on conventionally acceptable bond lengths and angles). More preferably, the nitrogen of B is separated from an amine of the group L2 by about 25 angstroms to about 50 angstroms. Preferred compounds of formula (IV) also have a log D between about xe2x88x923 and about 5. Using the above parameters, one skilled in the art can readily determine compounds of formula (IV) possessing the desired properties for an intended use.
Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd""s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March""s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Furthermore, it will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
In general, compounds of Formula (I) can be prepared as illustrated and described in Schemes A. 
A compound of Formula (I) is prepared by covalently attaching one equivalent of a compound of formula 1 with a compound of formula 2 where X is a linker as defined herein, FG1 is a functional group, FG2 is a functional group that is complimentary to FG1, PG is a protecting group, and FG2PG is a protected functional group, to give an intermediate of formula (II). Deprotection of the functional group on the linker, followed by reaction of resulting compound 3 with one equivalent of compound 4, then provides a compound of Formula (I). The reaction conditions used to link compounds 1 and 4 to compound 2 and 3 depend on the nature of the functional groups on compounds 1, 2, 3 and 4 which in turn depend on the type of linkage desired. Examples of the functional groups and the reaction conditions that can be used to generate a specific linkage is described below.
Reaction between a carboxylic acid of either the linker or the ligand and a primary or secondary amine of the ligand or the linker in the presence of suitable, well-known activating agents such as dicyclohexylcarbodiimide, results in formation of an amide bond covalently linking the ligand to the linker; reaction between an amine group of either the linker or the ligand and a sulfonyl halide of the ligand or the linker, in the presence of a base such as triethylamine, pyridine, and the like results in formation of a sulfonamide bond covalently linking the ligand to the linker; and reaction between an alcohol or phenol group of either the linker or the ligand and an alkyl or aryl halide of the ligand or the linker in the presence of a base such as triethylamine, pyridine, and the like, results in formation of an ether bond covalently linking the ligand to the linker.
Suitable dihydroxyl and dihalo starting materials useful for incorporating a group X into a compound of the invention are shown in the following table. Preferably, an alcohol is reacted with a ligand bearing a leaving group to provide an ether bond, while a dihalo compound is preferably reacted with an amine of the ligand to form a subatituted amine.
Typically, a compound selected for use as a ligand will have at least one functional group, such as an amino, hydroxyl, thiol or carboxyl group and the like, which allows the compound to be readily coupled to the linker. Compounds having such functionality are either known in the art or can be prepared by routine modification of known compounds using conventional reagents and procedures.
A compound of formula (a) wherein A is phenyl, pyridyl, and the like can be prepared as described in EP 747 355 and as described by Naito, R. et al., Chem. Pharm. Bull., 1998, 46(8), 1286.
L1xe2x80x94H+Raxe2x80x94Xxe2x80x94L2xe2x86x92(I)
A compound of formula (I) wherein L1 comprises a nitrogen that is bonded to X, can be prepared by alkylating a corresponding compound of formula L1xe2x80x94H wherein xe2x80x94H is bound to the nitrogen, with a corresponding compound of Raxe2x80x94Xxe2x80x94L2 wherein X and L2 have any of the values defined herein and Ra is a suitable leaving group. Suitable leaving groups an conditions for the alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley and Sons, New York. For example, Ra can be halo (e.g. chloro, bromo, or iodo), methylsulfonyl, 4-tolylsulfonyl, mesyl, or trifluoromethylsulfonyl.
Accordingly, the invention provides a method for preparing a compound of formula (I) wherein L1 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L1xe2x80x94H with a compound of Raxe2x80x94Xxe2x80x94L2 wherein X and L2 have any of the values defined herein and Ra is a suitable leaving group.
The invention also provides a compound of formula L1xe2x80x94H wherein L1, has any of the values defined herein. The following compounds are preferred compounds of formula L1xe2x80x94H: 
The invention also provides a compound of formula Raxe2x80x94Xxe2x80x94L2 wherein X, and L2 have any of the values defined herein and Ra is a suitable leaving group. The compound of formula L1xe2x80x94H can also be alkylated by treatment with an aldehyde of formula L2xe2x80x94Vxe2x80x94CHO (wherein xe2x80x94Vxe2x80x94CH2xe2x80x94 is equivalent to xe2x80x94Xxe2x80x94), under reductive alkylation conditions. Reagents and conditions suitable for carrying out the reductive alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley and Sons, New York).
Accordingly, the invention provides a method for preparing a compound of formula (I) wherein L1 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L1xe2x80x94H with a compound of formula L2xe2x80x94Vxe2x80x94CHO (wherein xe2x80x94Vxe2x80x94CH2xe2x80x94 has any of the values for xe2x80x94Xxe2x80x94 described herein).
L1xe2x80x94Xxe2x80x94Ra+Hxe2x80x94L2xe2x86x92(I)
A compound of formula (I) wherein L2 comprises a nitrogen that is bonded to X, can be prepared by alkylating a corresponding compound of formula L2xe2x80x94H wherein xe2x80x94H is bound to the nitrogen, with a corresponding compound of L1xe2x80x94Xxe2x80x94Ra wherein X and L1 have any of the values defined herein and Ra is a suitable leaving group. Suitable leaving groups an conditions for the alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley and Sons, New York. For example, Ra can be halo (e.g. chloro, bromo, or iodo), methylsulfonyl, 4-tolylsulfonyl, mesyl, or trifluoromethylsulfonyl.
Accordingly, the invention provides a method for preparing a compound of formula (I) wherein L2 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L2xe2x80x94H with a compound of L1xe2x80x94Xxe2x80x94Ra wherein X and L1 have any of the values defined herein and Ra is a suitable leaving group.
The compound of formula L2xe2x80x94H can also be alkylated by treatment with an aldehyde of formula L1xe2x80x94Vxe2x80x94CHO (wherein xe2x80x94Vxe2x80x94CH2xe2x80x94 is equivalent to xe2x80x94Xxe2x80x94), under reductive alkylation conditions. Reagents and conditions suitable for carrying out the reductive alkylation of an amine are known in the art (for example, see Advanced Organic Chemistry, Reaction Mechanisms and Structure, 4 ed., 1992, Jerry March, John Wiley and Sons, New York).
Accordingly, the invention provides a method for preparing a compound of formula (I) wherein L2 comprises a nitrogen that is bonded to X, comprising alkylating a corresponding compound of formula L2xe2x80x94H with a compound of formula L1xe2x80x94Vxe2x80x94CHO (wherein xe2x80x94Vxe2x80x94CH2xe2x80x94 has any of the values for xe2x80x94Xxe2x80x94 described herein).
It will be understood that the alkylation reactions in Schemes B and C can optionally be carried out using suitably protected derivatives of L1xe2x80x94H, L2xe2x80x94H, L1xe2x80x94Xxe2x80x94Ra, Raxe2x80x94Xxe2x80x94L2, L1xe2x80x94Vxe2x80x94CHO, and L2xe2x80x94Vxe2x80x94CHO. Suitable protecting groups as well as conditions for their incorporation and removal are known in the art (for example, see Greene, T. W.; Wutz, P. G. M. xe2x80x9cProtecting Groups In Organic Synthesisxe2x80x9d second edition, 1991, New York, John Wiley and sons, Inc.). Thus, a compound of formula (I) can also be prepared by deprotecting a corresponding compound of formula (I) bearing one or more protecting groups.
Accordingly, the invention provides a method for preparing a compound of formula (I) comprising deprotecting a corresponding compound of formula (I) that bears one or more protecting groups. The invention also provides an intermediate compound of formula (I) that bears one or more protecting groups.
Compounds of formula (I) can conveniently be prepared using combinatorial synthesis methods (e.g. solid phase and solution phase combinatorial synthesis methods) that are known in the art. For example, compounds of formula (I) can be prepared using combinatorial methods like those escribed in International Patent Application Publication Number WO 99/64043.
The compounds of this invention are muscarinic receptor antagonists or agonists. A preferred sub-groug of compounds of the invention are M2 muscarinic receptor antagonists. Accordingly, the compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of diseases mediated by these receptors such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and Alzheimer""s disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, hyper salvation syndromes, and the like.
The ability of the compounds of formula (I) to inhibit a muscarinic receptor (e.g. the M2 or M3 subtype) may be demonstrated using a variety of in vitro assays and in vivo assays known in the field, or may be demonstrated using an assay described in biological examples 1-6 below.
When employed as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, intravesicular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds described herein associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.001 to about 1 g, usually about 0.1 to about 500 mg, more usually about 1 to about 50 mg, of the active ingredient. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of Formula (I) above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.